Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1207 - 1217 |
| Number of pages | 11 |
| Journal | Cancer Immunology Research |
| Volume | 3 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2015 |
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Loss of host type-I IFN signaling accelerates metastasis and impairs NK-cell antitumor function in multiple models of breast cancer. / Rautela, Jai; Baschuk, Nikola; Slaney, Clare Y; Jayatilleke, Krishnath M; Xiao, Kun; Bidwell, Bradley N; Lucas, Erin C; Hawkins, Edwin; Lock, Peter; Wong, Christina S F; Chen, Weisan; Anderson, Robin L; Hertzog, Paul John; Andrews, Daniel Mark; Moller, Andreas; Parker, Belinda S.
In: Cancer Immunology Research, Vol. 3, No. 11, 2015, p. 1207 - 1217.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Loss of host type-I IFN signaling accelerates metastasis and impairs NK-cell antitumor function in multiple models of breast cancer
AU - Rautela, Jai
AU - Baschuk, Nikola
AU - Slaney, Clare Y
AU - Jayatilleke, Krishnath M
AU - Xiao, Kun
AU - Bidwell, Bradley N
AU - Lucas, Erin C
AU - Hawkins, Edwin
AU - Lock, Peter
AU - Wong, Christina S F
AU - Chen, Weisan
AU - Anderson, Robin L
AU - Hertzog, Paul John
AU - Andrews, Daniel Mark
AU - Moller, Andreas
AU - Parker, Belinda S
PY - 2015
Y1 - 2015
N2 - Metastatic progression is the major cause of breast cancer related mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1-/- mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1-/- mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host haematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating NK cell population. We find that in vivo stimulated NK cells derived from WT, but not Ifnar1-/- mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an anti-metastatic strategy.
AB - Metastatic progression is the major cause of breast cancer related mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1-/- mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1-/- mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host haematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating NK cell population. We find that in vivo stimulated NK cells derived from WT, but not Ifnar1-/- mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an anti-metastatic strategy.
UR - http://www.ncbi.nlm.nih.gov/pubmed/26198985
U2 - 10.1158/2326-6066.CIR-15-0065
DO - 10.1158/2326-6066.CIR-15-0065
M3 - Article
VL - 3
SP - 1207
EP - 1217
JO - Cancer Immunology Research
JF - Cancer Immunology Research
SN - 2326-6066
IS - 11
ER -